CD4 T cells help B cells produce antibodies following antigen challenge. This response classically occurs in germinal centers (GC) located in B-cell follicles of secondary lymphoid organs (SLO), a site of immunoglobulin isotype switching and affinity maturation. GC formation requires specialized CD4 T cells, T-follicular helper (Tfh) cells, which localize to follicles and provide B cells with survival and differentiation signals that are essential for B-cell maturation into memory and long-lived plasma cells. Pathogenic autoantibodies in human and murine lupus arise in a like manner. Although Tfh cells are critical for GC development, their genesis in humans, role in promotion of autoimmunity, and potential as therapeutic targets in SLE are incompletely understood. To address these issues, we dissected Tfh cell development and function, defining their transcriptional regulation, migration, and function in vivo in normal and lupus-prone mice and ex vivo in normal humans and patients with SLE.